Each year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of... Show moreEach year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of great importance to identify individuals with an increased risk for CRC. In this thesis, we evaluate the use of molecular pathology for identifying individuals with an increased risk for CRC based on their genetic makeup, and for generating insight into the tumorigenesis of familial CRC. We conclude that molecular pathology has a high potential for playing an active role in identifying individuals with CRC predisposing syndromes in a diagnostic setting as well as in studying tumorigenesis of CRC in a research setting. Tests which are readily applicable and straightforward, are now extensively used in our daily molecular pathology diagnostics. In the research setting, molecular pathology will be an important player in study the contribution to an increased CRC risk of the susceptibility alleles that are being identified. Furthermore, we now argue that the distinct tumor profiles that we found are convincing examples that molecular pathology approaches are also crucial in the characterization and elucidation of unresolved familial causes of CRC. Show less
Diffuse large B cell lymphoma is the most common type of non-Hodgkin lymphoma of which 40% present at extra-nodal sites including immune privileged sites such as the testis and the central nervous... Show moreDiffuse large B cell lymphoma is the most common type of non-Hodgkin lymphoma of which 40% present at extra-nodal sites including immune privileged sites such as the testis and the central nervous system (CNS). Loss of Human Leucocyte Antigen (HLA) expression has been described in many different tumour types as a mechanism to evade anti-tumour immune responsen. In testicular and CNS lymphomas HLA class I and II expression was very commonly observed in contrast to nodal, stomach and skin lymphomas that expressed HLA in most of the cases. Loss of HLA-DR and DQ expression was often due to homozygous deletions of the corresponding genes. Loss of class I expression was often caused by loss of Beta-2-microglobulin expression and hemizygous deletions. Despite their immune privileged status, the testicular and CNS lymphomas showed high numbers of activated cytotoxic T cells, suggesting that these lymphomas are highly immunogenic. DNA-typing for HLA-DR and DQ polymorphisms in testicular and nodal lymphomas revealed a positive association of testicular lymphomas with HLA-DRB1*12 and a negative association of nodal lymphomas with HLA-DRB1*07. Both testicular and nodal lymphomas showed a positive association with HLA-DRB1*15. No significant relationship was found between the different haplotypes and the occurrence of homozygous deletions in the testicular lymphomas. Show less